Chapter 22 Alpha Substitution and Condensations of Enols and Enolate Ions Jo Blackburn Richland College, Dallas, TX Dallas County Community College District 2006, Prentice Hall Organic Chemistry, 6 th Edition L. G. Wade, Jr.
Dec 16, 2015
Chapter 22Alpha Substitution and
Condensations of Enolsand Enolate Ions
Jo BlackburnRichland College, Dallas, TX
Dallas County Community College District2006,Prentice Hall
Organic Chemistry, 6th EditionL. G. Wade, Jr.
Chapter 22 2
Alpha SubstitutionReplacement of a hydrogen on the carbon
adjacent to the carbonyl, C=O.
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Chapter 22 3
Condensation withAldehyde or Ketone
Enolate ion attacks a C=O and the alkoxide is protonated. The net result is addition.
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Chapter 22 4
Condensation with Esters
Loss of alkoxide ion results in nucleophilic acyl substitution.
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Chapter 22 5
Keto-Enol Tautomers
• Tautomers are isomers which differ in the placement of a hydrogen.
• One may be converted to the other.
• In base:
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Chapter 22 7
Equilibrium Amounts• For aldehydes and ketones, the keto
form is greatly favored at equilibrium.
• An enantiomer with an enolizable hydrogen can form a racemic mixture.
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Chapter 22 8
Acidity of -Hydrogens
• pKa for -H of aldehyde or ketone ~20.
• Much more acidic than alkane or alkene (pKa > 40) or alkyne (pKa = 25).
• Less acidic than water (pKa = 15.7) or alcohol (pKa = 16-19).
• In the presence of hydroxide or alkoxide ions, only a small amount of enolate ion is present at equilibrium. =>
Chapter 22 9
Enolate Reaction
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As enolate ion reacts withthe electrophile, the equilibriumshifts to produce more.
Chapter 22 10
Acid-Base Reactionto Form Enolate
Very strong base is required for complete reaction. Example:
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Chapter 22 11
Halogenation• Base-promoted halogenation of ketone.• Base is consumed.• Other products are water and chloride ion.
OH_
O
H
HO
H
_O
H
ClCl Cl
=>
Chapter 22 12
Multiple Halogenations
• The -halo ketone produced is more reactive than ketone.
• Enolate ion stabilized by e--withdrawing halogen.
O
H
ClCl2
OH , H2O_
O
Cl
Cl
O
Cl
ClCl
O
Cl
ClClCl
=>
Chapter 22 13
Haloform Reaction
• Methyl ketones replace all three H’s with halogen.
• The trihalo ketone then reacts with hydroxide ion to give carboxylic acid.
Iodoform,yellow ppt. =>
C
O
CH3excess I2
OH-
C
O
CI3 OH-
C
O
OH
CI3-
C
O
O-
HCI3
Chapter 22 14
Positive Iodoformfor Alcohols
If the iodine oxidizes the alcohol to a methyl ketone, the alcohol will give a positive iodoform test.
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Chapter 22 15
Acid CatalyzedHalogenation of Ketones
• Can halogenate only one or two -H’s.
• Use acetic acid as solvent and catalyst.
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Chapter 22 16
Aldehydes and Halogens
Halogens are good oxidizing agents and aldehydes are easily oxidized.
C
O
H + Br2 C
O
OHH2O
+ 2 HBr
=>
Chapter 22 17
The HVZ ReactionThe Hell-Volhard-Zelinsky reaction replaces
the -H of a carboxylic acid with Br.
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Chapter 22 18
Alkylation
• Enolate ion can be a nucleophile.
• Reacts with unhindered halide or tosylate via SN2 mechanism.
O
H
HO
H(i-Pr)2N-Li+
CH3 Br
O
H
CH3
=>
Chapter 22 19
Stork Reaction• Milder alkylation method than using LDA.
• Ketone + 2 amine enamine.
• Enamine is -alkylated, then hydrolyzed.
O
H
H NH
H+
H
HHON
H+
NH
H+
N
H
CH3 Br
+N
H
N
HCH3
H3O+
O
CH3
HBr
-
+ NH
H
+ =>
Chapter 22 21
Aldol Condensation
• Enolate ion adds to C=O of aldehyde or ketone.
• Product is a -hydroxy aldehyde or ketone.
• Aldol may lose water to form C=C.
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Chapter 22 24
Crossed AldolCondensations
• Two different carbonyl compounds.
• Only one should have an alpha H.
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Chapter 22 25
Aldol Cyclizations• 1,4-diketone forms cyclopentenone.
• 1,5-diketone forms cyclohexenone.
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Chapter 22 27
Claisen CondensationTwo esters combine to form a -keto ester.
CH3 O C
O
CH R
CH3OC
O
CH2R
CH3 O C
O
CH R
CH3OC
O
CH2R
enolate ionpKa = 24
CH3 O C
O
CH Rbase
CH3 O C
O
CH2 R
=>
_
CH3 O C
O
C C
R
CH2R
O
pKa = 11
_OCH3
CH3 O C
O
CH C
R
CH2R
O
Chapter 22 28
Dieckmann Condensation• A 1,6 diester cyclic (5) -keto ester.
• A 1,7 diester cyclic (6) -keto ester.
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Chapter 22 29
Crossed Claisen
• Two different esters can be used, but one ester should have no hydrogens.
• Useful esters are benzoates, formates, carbonates, and oxalates.
• Ketones (pKa = 20) may also react with an ester to form a -diketone.
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Chapter 22 30
-Dicarbonyl Compounds
• More acidic than alcohols.
• Easily deprotonated by alkoxide ions and alkylated or acylated.
• At the end of the synthesis, hydrolysis removes one of the carboxyl groups.
CH3CH2O C
O
CH2 C
O
OCH2CH3
malonic ester, pKa = 13
CH3 C
O
CH2 C
O
OCH2CH3
acetoacetic ester, pKa =11=>
Chapter 22 31
Malonic Ester Synthesis• Deprotonate, then alkylate with good
SN2 substrate. (May do twice.)
• Decarboxylation then produces a mono- or di-substituted acetic acid.
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Chapter 22 33
Conjugate Additions
• When C=C is conjugated with C=O, 1,2-addition or 1,4-addition may occur.
• A 1,4-addition of an enolate ion is called the Michael reaction.
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Chapter 22 34
Michael Reagents
• Michael donors: enolate ions stabilized by two electron-withdrawing groups.-diketone, -keto ester, enamine,
-keto nitrile, -nitro ketone.
• Michael acceptors: C=C conjugated with carbonyl, cyano, or nitro group.conjugated aldehyde, ketone, ester,
amide, nitrile, or a nitroethylene. =>
Chapter 22 35
A Michael Reaction
Enolates can react with ,-unsaturated compounds to give a 1,5-diketo product.
CH3CH2O C
O
CH
COOC2H5
_
CHH
C C
H O
CH3 CH3CH2O C
O
CH
COOC2H5
CH2C
H
C
O
CH3
_
H OC2H5
CH3CH2O C
O
CH
COOC2H5
CH2C
H
C
O
CH3
H
H3O+
heatHO C
O
CH CH2C
H
C
O
CH3
H
COOH
HO C
O
CH2 CH2C
H
C
O
CH3
H =>-keto acid
Chapter 22 36
Robinson Annulation
A Michael reaction to form a -diketone followed by an intramolecular aldol condensation to form a cyclohexenone.
CH3
H
O+
CH
H
C H
COH3C
_OH
CH3
O
=>